1. DPP4-Inhibition and Coronary Artery Disease Mary Anne Lim-Abrahan, MD, FPCP, FPSEM Professor, Endocrinology, Diabetes & Metabolism Dept. of Medicine, UP College of Medicine

2. DPP-4 Inhibition and CAD The Heart in Diabetes -- Epidemiology -- Energy needs of the Heart The Role of Incretins in the Cardiovascular Continuum - Effects on risk factors, LVH ischemia, AMI, remodeling, CHF and survival Mechanisms for GLP-1 Cardioprotection

3. Admission Glucose and Mortality M Kosiborod et al. Circulation 2005;111;3078-3086. N=141,680 Medicare patients discharged 1/94 – 12/96

4. MenWomen % Mortality 1-Year Mortality in Diabetic and Nondiabetic Subjects after a First MI Miettinen H et al. Diabetes Care 1998;21:69-75

5. Diabetes Doubles Early MI Mortality; Despite in Advances in Cardiac Care Braunwald NEJM 1997;337:1360-69 Defribillation Hemodynamic monitoring “LYTIC” Reperfusion Beta-blockade Aspirin (before 1962) (1962-1984) (1984-1999) (2000-present)

6. Diabetes and IGT are present in AMI Consecutive patients with AMI- n=181. OGTT done in all. The 80% after OGTT 25% DM by OGTT 35% IGT by OGTT 40% normal by OGTT If all patients are tested= 2/3 of non diabetics- we are not doing anything about it Norhammar A Lancet 2002; 357: 2140-44 Diabetics excluded No diabetes by history

7. DIABETIC HEART DISEASE Mechanisms Diabetic Heart Disease 1. Abn load due to arterial disease 2. Metabolic Effects due to FFA, Insulin resistance 3. Structural – Myocardial fibrosis and ECM changes 5. Autonomic dysfunction due to reduced HR 4. Reduced perfusion due to small vessel disease Assuming subclinical CAD and LVH excluded Fang et al. Endocr Rev2004

8. Diabetes, Insulin Resistance and the Risk of Developing Heart Failure Type 2 diabetes independently confers ~2- fold ↑ risk in men and 3-5-fold ↑ risk in women 1234 Insulin resistance independently confers ~1.5 increase in risk 5 Both diabetes and IR have a synergistic interaction with other risk factors, especially HTN and CAD 1Kannel et al, Am J Cardiol 1974; 2Levy et al, JAMA 1996; 3Gottdiener et al, J Am Coll Cardiol 2000; 4Nichols et al, Diabetes Care 2001; 5Ingelsson et al, JAMA 2005

9. Diastolic Dysfunction in DM DD is most frequently identified in diabetic patients with normal systolic function as an incidental finding at echocardiography Complaints include dyspnea, limited exercise capacity  often ascribed to obesity or deconditioning and not recognized as a symptom. Delayed or impaired relaxation is earliest and most common change.

10. Kaplan-Meier Analysis of Diastolic Dysfunction and Subsequent HF in Diabetic Patients Aron, M JACC 55, No. 4, 2010

11. Kaplan-Meier Analysis of Diastolic Dysfunction and Death in Diabetic Patients Aron, M JACC 55, No. 4, 2010

12. Energy Needs of the Heart  Continuous need for large amounts of ATP Heart turns over 5 kg/day of ATP(!) – completely turns over ATP supply every 13 seconds(!)  Potential fuels – “Metabolic omnivore” Free fatty acids (FFA) 70% in normal hearts Glucose Used in stressed/injured heart Lactate Up to 60% of fetal energy production

13. Responses to Injury and Insulin Resistance RM Witteles and MB Fowler. J Am Coll Cardiol 2008; 51: 93-102

14. Impact of Insulin Resistance on Myocardial Metabolism: Importance of FF Acid Generation FFA=Free fatty acids. Adapted from Oliver MF et al. Lancet. 1994;343:155-158. CV stress Catechols, Cortisol  Lipolysis  Plasma FFA Glucose  Insulin Coronary occlusion Lysophospholipids Ca 2+ overloadEnzyme loss  Glycolysis  Glucose oxidation Membrane damage Arrhythmias Phospholipids TG FFA Acyl CoA Acylcarnitine

15. Diabetic Hearts Rely Almost Completely on FFA Belke et al. Am J Physiol Endocrinol Metab 2000; 279: E1104-E1113.

16. Substrate Shifts in the Failing Heart Glucose metabolism: increased FFA metabolism: decreased Result: More efficient energy utilization Fundamental point: –These shifts are inhibited in the setting of insulin resistance! Therefore... –Insulin is important for the healthy heart for transport and utilization of glucose –Insulin is even more important for the failing heart which is more dependent on glucose metabolism. –Insulin resistance is particularly bad in the failing heart.

17. Diabetic hearts are less powerful... can be overcome with GLUT-4 overexpression Belke et al. Am J Physiol Endocrinol Metab 2000; 279: E1104-E1113

18. General features of insulin signal transduction pathways R Muniyappa et al. Endocrine Reviews 2007; 28(5): 463-491. INSULIN RESISTANCE INSULIN SENSITIVE

19. The concept of metabolic modulation to induce a shift towards glucose utilization may be a particularly useful strategy for these patients.

21. AMI Pain-Related Burst of Catecholamine 1. Acts on adipose tissue to mobilize FFAs 2. Acutely inhibits the release of insulin from the pancreas 3. AMI is diabetogenic. Causes hyperglycemia. Vetter NJ. Lancet.1974;1:284-288. 4. Elevated FFAs are preferentially oxidized by skeletal and cardiac muscle, hence inhibiting the uptake and oxidation of glucose ( Breham A. Diabetes.2006; 55:136-40) and directly contributing to insulin resistance  hyperglycemia (Whitteles RM. J Am Coll Cardiol.2008;51:93-102)

22. Pain-Related Burst of Catecholamine Catecholamines increased glucose by promoting hepatic glycogenolysis Sustained β-adrenergic stimulation directly promotes insulin resistance by inhibition of insulin signaling at the level of protective kinases. Morisco C.Cardiovasc Res. 2007; 76:453-464. Early β-blockade can reduce FFA uptake by the failing myocardium Walhaus TR. Circ 2001;103:2441-2446 and lessen FFA accumulation in the ischemic- reperfused heart. Igarashi N. Circ J 006;70:1509-1514. β-blockade may have adverse hemodynamic consequences including cardiogenic shock and hypotension. Chen ZM.Lancet.2005;366:1622-1632. Giving β-blockade after 3 hours not of much benefit. Gersh BJ. JAMA 2005;293:979-986.

23. Adverse Effects of FFAs in AMI Mechanisms: Membrane-damaging detergent properties of FFAs. Oliver MF. Lancet.1994;343:155-158. Increased oxygen demand. How OJ. Diabetes2006;55: 466-473. The metabolic inefficiency leads to contractile abnormalities and adverse left ventricular remodeling. How OJ. Diabetes. 2006;55: 466-473.

24. Changes in Oxygen Demand on Switching from Carbohydrate to Fatty Acid Metabolism Normal Heart- 11% increased in oxygen demand. Ashrafian H. Circulation. 2007;116:434-448. Diabetic Hearts perfused with FFAs- 85% increase with “pronounced oxygen wastage” coupled with decreased cardiac efficiency. How OJ. Diabetes2006;55: 466-473. This is due to mitochondrial uncoupling Essop F. Eur Heart J.2004;25:1765-1768 which underlies the FFA- induced increased in myocardial oxygen consumption Mjos OD. J Clin Invest,1971;50:1869-1873 and local heat production (Mjos OD. Scan J Clin Lab Invest. 1971;28:389-393)

25. DPP-4 Inhibition and CAD The Heart in Diabetes -- Epidemiology -- Energy needs of the Heart The Role of Incretins in the Cardiovascular Continuum - Effects on risk factors, LVH ischemia, AMI, remodeling, CHF and survival Mechanisms for GLP-1 Cardioprotection

26. GLP-1R expression in mouse cardiac and vascular tissues GLP-1R expression on cardiomyocytes GLP-1R expression on endocardium Ban K Circulation. 2008;117:2340-2350 GLP-1R expression on vascular endothelium, and SMCs

27. The Cardiovascular Disease Continuum VJ Dzau et al. Circulation 2006; 114: 2850-2870

28. The Cardiovascular Disease Continuum VJ Dzau et al. Circulation 2006; 114: 2850-2870

29. GLP-1 and Cardiovascular Effects Weight loss associated with GPL-1 (exenatide) may have indirect benefit on CV risk including blood pressure, cholesterol levels, inflammatory markers and insulin resistance. Blonde L Diabetes Obes Metab 2006;8:436-447. In 217 patients from open-label extensions of various exenatide trials, modest benefit on certain CV risk factors. Klonoff DC. Curr Med Res Opin 2008;24:275-286. - trend to decrease SBP; significant decrease DBP - decrease TG (-44.4 mg/dL), TC (-10.8 mg/dL) and LDL-C (-11.8 mg/dL) and increase HDL-C(8.5 mg/d/L) -↓ CRP from 3.2 mg/L  1.35 mg/L

30. Liraglutide Associated with weight loss Associated with decrease in systolic blood pressure Decreases visceral fat Favorable effect on CRP, etc LEAD Programme, 2009

31. GLP-1 Improves Endothelial Dysfunction Type 2 DM Patients with CAD *P 0.05 Nystrom T. Am J Physiol Endocrinol Metab 287: E1209–E1215, 2004

32. The Cardiovascular Disease Continuum VJ Dzau et al. Circulation 2006; 114: 2850-2870

33. GLP-1 Therapy vs GIK These effects are predicated on ambient glucose concentration and are mitigated at plasma glucose concentrations <70 mg/dL, minimizing risks of hypoglycemia and the need for glucose infusion. Thus, the pharmacological properties of GLP- 1 are attractive as a means to stimulate myocardial glucose uptake during post- ischemic contractile dysfunction.

34. Glucose-Dependent Actions of GLP-1 in Patients With Type 2 Diabetes

35. GLP-1 May Protect Against Infarction GPL-1 administered prior to ischemia can activated glycolysis and decrease pyruvate and lactate in the myocardium. GLP-1 can protect myocardium by reducing infarct size when given throughout ischemia and reperfusion This protective effect is in addition to activation of prosurvival kinases like PI3K /Akt. The prosurvival kinases are part of the Reperfusion Injury Salvage Kinase pathway (RISK pathway) associated with both precondtioning protection as well as protection against reperfusion injury. Thus GLP-1 may protect against infarction when given before ischemia (as a preconditioning mimetic) or at reperfusion Bose AK Cardiovascular Drugs and Therapy 19 9–11 2005

36. Myocardial infarction in hearts that have been subjected to 35 min of left main coronary artery occlusion followed by 120 min of reperfusion AK Bose et al. Diabetes 2005; 54: 146-151.

37. GLP-1 Decreases Myocardial Infarct Size AK Bose et al. Diabetes 2005; 54: 146-151. In vitro myocardial infarct size In vivo myocardial infarct size

38. Exenatide Reduces Infarct Size in a Porcine Model of Ischemia and Reperfusion Injury Blue - nonthreatened myocardium, red - noninfarcted area within AAR, white - myocardial infarction. Timmers L. JACC 2009;53(6)501-510 Infarct Size (% of AAR) Infarct Size (% of LV) AB p = 0.031 p = 0.047 C PBSExenatide D

39. Proof of Concept Clinical Study – AMI Small trial with GLP-1 in AMI and LV dysfunction after successful reperfusion – GLP-1 started after reperfusion. 21 patients with ST segment elevation MI and impaired LV systolic function (LVEF<40%) were undergoing primary PCI Nikolaidis LA. Circ 2004:109:962-965

40. Effects of GLP-1 in Patients with AMI and LV Dysfunction After Successful Reperfusion Primary objective - safety and efficacy of a 72-hour infusion of GLP-1 (1.5 pmol/kg per minute) added to background therapy in 10 patients with AMI and LV ejection fraction (EF) <40% after successful primary angioplasty compared with 11 control patients. Inclusion Critiria - Patients presenting within 6 hrs from symptom onset, with Killip class II–IV clinical presentation and LV ejection fraction (EF) <40%, who were treated with primary angioplasty Patient characteristics - Both groups had severe LV dysfunction at baseline (LVEF=29±2%). Parameters - Echocardiograms were obtained after reperfusion and after the completion of the GLP-1 infusion. Nikolaidis LA. Circ 2004:109:962-965

41. Changes in LVEF and in regional wall motion score at the per- infarct zone after 72 hours of rGLP-1 infusion LA Nikolaidis et al. Circulation 2004; 109: 962-965.

42. Results- Mortality/Morbidity rGLP-1 Treated N=10 Controls N=11 p value In-Hospital Mortality Rate 1 (10%)3 (27%) CV Death02 (18%); VF, Cardiogenic Shock Length of Hospital Stay (days) 6.1 ± 1.39.8 ± 1.50.02 CCU Days3.1 ± 45.1 ± 1.0

43. Conclusion GLP-1 infusion improved regional and global LV function in patients with AMI and severe systolic dysfunction after successful primary angioplasty. rGLP-1 may contribute to improved outcomes through non–glucose-dependent mechanisms. These include reductions in plasma NEFA levels that have been implicated in arrhythmogenesis. Kavianipour M Peptides 2003:24:560-578. rGLP-1 may improve endothelial function and microcirculatory integrity, as suggested by the higher peak creatine phosphokinase, consistent with greater washout, in the rGLP-1–treated patients, despite comparable baseline regional and global LV dysfunction in both groups.

44. The Cardiovascular Disease Continuum VJ Dzau et al. Circulation 2006; 114: 2850-2870

45. GLP-1 Improves the Failing Heart In failing myocardium, Shannon’s group reported beneficial effects of LV contractile function. -- in a canine model of pacing-induced dilated CM, 48 hour infusion of GLP-1 improved myocardial insulin sensitivity and glucose uptake; increased SV and CO, and decreased LVED volume, HR and systemic vascular resistance. Nikolaidis LA. Circulation 2004; 110:955-961. -- in a canine model of myocardial stunning, GLP-1 improved regional contractile function. Nikolaidis LA. J Pharmacol Exp Ther 2005; 312:303-308.

46. Hemodynamic Effects of Continuous infusion of rGLP-1 Failing heart has a preference for glucose as its metabolic substrate Examine impact rGLP-1 on LV and systemic hemodynamics and myocardial substrate uptake - 16 conscious dogs with advanced DCM vs 8 controls May provide a mechanism for overcoming myocardial insulin resistance and enhancing myocardial glucose uptake. Nikolais LA Circulation 2004;110:955-961

47. rGLP-1 improves myocardial glucose uptake, oxygen consumption, and CBF responses at matched levels of hyperinsulinemia, consistent with insulinomimetic effect LA Nikolaidis et al. Circulation 2004; 110: 955-961

48. 12 patients, chronic HF (NYHA III & IV) 5 weeks of chronic GLP-1 infusion increased LVEF from 21% to 27%, augmented maximum myocardial oxygen consumption and improved the 6-minute walk test and QOL in both diabetic and non-diabetic patients. No significant changes in any of the parameters in the control patients on standard therapy. Benefits were seen in both diabetic both diabetic and non-diabetic patients. Sokos GG. J Card Fail 2006;12:694-699.

49. GLP-1 Therapy improves Heart Failure –Class III-IV GG Sokos. J Cardiac Fail 2006; 12(9): 694-699.

50. GLP-1 Therapy Improves Heart Failure GG Sokos. J Cardiac Fail 2006; 12(9): 694-699.

51. The Cardiovascular Disease Continuum VJ Dzau et al. Circulation 2006; 114: 2850-2870 Survival???

52. SHHF rats randomized to receive intraperintoneal continuous infusion of GLP-1 had better survival compared with control I Poornima. Circ Heart Fail 2008; 1: 153-160

53. GLP-1 treatment was associated with significantly less myocyte apoptosis. There was no difference in nonmyocyte apoptosis. I Poornima. Circ Heart Fail 2008; 1: 153-160

54. Mechanisms for GLP-1 Cardioprotection Improvement of risk factors – weight loss, BP reduction, improved lipids and PPG reduction Improved vascular FMD. Increases myocardial glucose uptake Recruitment of intracellular signaling pathways involving Akt, Erk1/2, p70S6K and AMPK as well as the downstream phosphorylation and inhibition of the pro-apoptotic protein BAD, etc. Decreased myocyte apoptosis Strongly cardioprotective in multiple preclinical models

55. Incretin-based therapies in Type 2 Diabetes Mellitus

56. Cardiovascular risk factors and DPP-4 inhibition Effective control of PPG Reduction of postprandial lipids, especially chylomicrons and TGs Body weight – no effect or slight reduction Preclinical data- modest but significant cardioprotection in vivo

57. DPP-4 Inhibition and CAD The Heart in Diabetes -- Epidemiology -- Energy needs of the Heart The Role of Incretins in the Cardiovascular Continuum - Effects on risk factors, LVH ischemia, AMI, remodeling, CHF and survival Mechanisms for GLP-1 Cardioprotection